In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the tissue. Transport of the infused material is dominated by convection, which enhances drug penetration into tissue compared with diffusion mediated delivery. One drawback of CED is that larger proteins and compounds may interact with components of the extracellular matrix and/or cell membrane, resulting in inhibition of their transport. These compounds may also be cleared by capillaries, internalized by untargeted cells, or enzymatically degraded, thus not reaching their target.
Brain tissue is more poroelastic in that it deforms in response to local pressure. Pressure associated with infusion by needles can cause the brain tissue to separate away from the needle, opening a gap for material to flow back out. Conventional CED eliminates most of this deformation, but the area of delivery is still limited as noted above.
CED has emerged as a leading investigational delivery technique for the treatment of several disorders, including glioblastoma multiforme, a high-grade glioma that presents an especially poor prognosis for patients. CED bypasses the blood-brain barrier by infusing compounds through a needle or microcatheter directly into brain parenchyma or brain tumor. The clinical trials show mixed results and suggest that the outcome of the therapy depends strongly on the extent of penetration of the drug into the brain, which is determined by infusion velocity, the relative rates of convection and elimination during CED, and tissue properties. To increase the infusion velocity special micro-catheter and flexible designs have been constructed to reduce backflow of drug between the tissue and needle-shaft interfaces. To reduce the elimination rate and thereby extend the penetration distance, infused compounds have been incorporated into nanoparticles such as liposomes or polymeric beads, which protect the compounds during transport. However, backflow of drug during CED treatment still remains a critical problem in clinical practice and the transport of nanoparticles through the brain is hindered, because the size of the nanoparticles is comparable to the size of a typical “pore” of the extracellular space. Furthermore, it can be difficult to control the spatial distribution of infused molecules and nanoparticles when tissue characteristics vary within the treatment region, such as in heterogeneous tissue and near white matter tracts in the brain. There is therefore a need in the art for a delivery device that reduces backflow, increases the penetration distance and provides control over the spatial distribution of the infused drug. Such a delivery device could significantly improve the efficacy of CED in clinical practice.
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.